Transdermal therapeutic system with nicotine and addition of monoterpene ketones

ABSTRACT

A transdermal therapeutic system having a backing layer, at least one nicotine-containing layer ore zone, which may have pressure-sensitive properties, as well as a removable protective layer is characterized by a content of at least one essential oil extracted from a mint species, or at least one monoterpene ketone contained in these essential oils.

The present invention relates to the addition of odour-improvingsubstances to transdermal therapeutic systems (TTSs) containingnicotine. More particularly it relates to nicotine-comprising TTSscontaining such additives, as well as to processes for masking theunpleasant smell of such TTSs, as well as to the use of odour-improvingsubstances for masking the unpleasant smell of such TTSs caused by thenicotine content.

Worldwide, nicotine-containing TTSs are widely used in smoking cessationtreatment. However, the systems available on the market exhibit adistinct nicotine smell, which is perceived especially when removing thesystems from the package and upon application thereof.

In the course of the storage period of typically 2 to 3 years, owing topartial degradation, a marked intensification of this smell and a changeup to subjectively very unpleasant types of smells can occur.

WO 95/08324 A1 describes a process for making TTSs of at least twolayers, using a highly volatile ingredient as exclusive solvent. TheseTTSs may contain various active agents, including nicotine as well as,inter alia, menthol or other volatile terpene derivatives, as skinpenetration enhancer. No special action of these additives with respectto smell in nicotine-comprising TTSs has been described. As regards the“volatile terpene derivatives” no differentiation is made betweenmonoterpene alcohols and monoterpene ketones.

EP 0 356 382 A2 discloses TTSs based on certain block copolymers,wherein also nicotine may be used as an active agent. To improve skinpenetration, eucalyptol or eucalyptus oils are proposed, putting specialemphasis on cineol as main component; ingredients of mint oils are notconsidered. The aspect of the unpleasant smell of nicotine-comprisingpatches has likewise not been considered.

U.S. Pat. No. 5,599,554 A concerns the transmucosal or transdermalapplication of nicotine, wherein the compositions employed may alsocontain odoriferous substances or flavours. The characteristic smell ofnicotine is mentioned, it us true, but it is not described as being ofdisadvantage. Aromatic compounds such as menthol or eucalyptol, but notessential mint oils or terpene ketones, are mentioned as optionalingredients. No indication is made of the function of those additives.Presumably, they serve to improve taste in oral administration forms.

U.S. Pat. No. 5,593,684 A describes a method for treatment based on thesimultaneous transmucosal and transdermal administration of nicotine.Here, terpene-containing plant secretions are employed as “etherialoils” in lozenges for oral application in order to mask the unpleasanttaste of nicotine.

U.S. Pat. No. 4,933,184 concerns TTSs with improved transdermal activesubstance delivery, inter alia for nicotine, with menthol being utilizedas enhancer; no mention is made of other substances occurring inetherial oils of mint species, e.g. monoterpene ketone. A mint oil wasexamined as enhancer, as an alternative to menthol, but surprisingly didnot yield that effect. As for the rest, this publication merely relatesto the improvement of active substance permeation, not to a process forimproving the smell of TTSs.

It is thus the object of the present invention in nicotine-containingTTSs according to the introductory part of claim 1, to neutralise thischaracteristic smell, or mask it with a more pleasant smell, by addingsuitable odoriferous substances.

The solution of this task has now been found in the addition ofessential oils of various mint species or of components thereof,especially of monoterpene ketones. In accordance with the invention,these additives can be used to mask or improve the unpleasent smell ofnicotine-comprising TTSs. The TTSs according to the invention have acontent of at least one essential oil extracted from a mint species, orof a monoterpene ketone occurring in these essential oils.

The components of the essential oils of various mint species aredominated by products of the terpene metabolism, more precisely bymonoterpenes.

Mint oils are generally characterized by their pleasant, refreshingsmell. Examples of oils used are peppermint oil, spearmint oil orpoleimin oil, each extracted from different plants.

The characteristic monoterpenes contained in these oils can besubdivided into monoterpene alcohols and monoterpene ketones.

Typical monoterpene alcohols are: menthol, isomenthol, neomenthol,neoisomenthol and isopulegol. Typical monoterpene ketones are: menthone,isomenthone, carvone, piperitone, pulegone and isopulegone. Practicallyall of these representatives exist as enantiomers both in an opticallylevorotatory and a dextrorotatory form.

As representatives of this group the essential oils of peppermint (OleumMenthae peperitae), spearmint (Oleum Menthae crispae) and (Japanese)mint (Oleum Menthae arvensis) were examined.

Peppermint oil and especially mint oil are dominated by monoterpenealcohols, especially menthol. Spearmint oil, by contrast, contains aboveall monoterpene ketones, especially carvone (cf. monograph“Pfefferminzöl” [Peppermint oil] in the European Pharmacopeia 1997;monograph “Minzöl” [Mint Oil] in the German Pharmacopeia 1997; as wellas G. Schneider: Pharmazeutische Biologie [Pharmaceutic Biology], 2nded. 1988, BI Wissenschaftsverlag, S. 342–345).As single substances, (−)-menthol and (−)-menthone were tested astypical monoterpene alcohol and typical monoterpene ketone,respectively.

EXAMPLES

To examine the effect of such additives, a simplified smelling-testmodel was devised.

Nicotine was mixed in a concentration of 7%-wt. with miglyol 812.Miglyol 812 is a saturated triglyceride serving as an odourless carrier.The concentration of 7%-wt. of nicotine corresponds approximately to theactive substance concentration used in TTSs of 5–10%-wt. For nicotine inmiglyol, a vapour pressure comparable to that of TTSs, and thus asimilar intensity of smell, results. To this test mixture were added 5test substances or test mixtures:(−)-Menthol, (−)-menthone, peppermint oil (quality according to EuropeanPharmacopeia), spearmint oil (quality according to DeutscherArzneimittel Codex DAC [German Codex of Pharmaceutics] and mint oil(quality according to German Pharmacopeia).

The quantities added amounted to 0.5, 1.0 and 2.0%-wt. in each case.

This yielded 15 test samples. In addition, one sample was preparedwithout odour-improving additive.

These 16 sample were assessed by 6 subjects as to odour, with the kindand amount of the respective additive not being known to the subjects.

The assessment criteria and rating numerals comprise:

1. Nicotine smell: imperceptible (4); faint (3); moderate (2); distinct(1) 2. Overall impression: unpleasant (1); neutral (2); pleasant (3);fragrant (4)

The assessment of the overall impression was multiplied by the factor 2,for greater emphasis as against the nicotine smell, before adding thetwo values for each sample and person. Higher values signify a morefavourable assessment. The rating numerals were used to form the meanvalue. The theoretical minimal value is 3.0 and the theoretical maximumvalue is 12.0.

The results are shown in Table 1:

Test produkt/Amount 0.5%-wt. 1.0%-wt. 2.0%-wt. (−)-Menthol 4.0 4.1 4.9(−)-Menthone 6.6 6.4 8.6 Peppermint oil 6.9 8.7 9.3 Spearmint oil 7.37.7 9.6 Mint oil 6.0 7.0 9.0

The product without additive yielded the value 4.0.

A graphic representation of the results is shown in FIG. 1.

This shows a very surprisingly clear advantage of menthone over menthol.The 1 ss favourable results of mint oil, which is dominated by menthol(G. Schneider; Pharmazeutische Biologie, 2nd ed. 1988, BIWissenschaftsverlag, p. 345) as compared to peppermint oil, typicallycontaining up to 32% of menthone (European Pharmacopeia 1997), issupportive of these findings.

Finally, spearmint oil, which is dominated by carvone and is practicallyfree from menthol, yielded the best results.

Overall, this demonstrates a clear advantage of monoterpene ketones, ormixtures of monoterpene alcohols and monoterpene ketones, over puremonoterpene alcohols.

The practical realisation of adding the substances according to theinvention to nicotine-containing TTSs meets with certain difficultiesbecause of the high volatility of the substances; however, thesedifficulties can be eliminated by observing the teaching of PCT/WO95/08324.

The quantity of monoterpene ketone(s) or of essential oil contained inthe nicotine-comprising matrix of the odour-improved TTSs according tothe invention amounts to 0.1 to 5.0%-wt., preferably 0.5 to 2%-wt.

Thus, the addition of substances according to the present invention tonicotine-containing TTSs constitutes a useful means for improving theunpleasant smell of such TTSs.

The TTSs possessing the features as described in the introductory partof claim 1 are characterized, as mentioned above, by a content of atleast one essential oil extracted from a mint species, or a monoterpeneketone occurring in these essential oils.

Preferably the monoterpene ketone is one from the group of carvone,dihydrocarvone, menthone, isopulegone, isomenthone, neomenthone,neoisomenthone or piperitone. The monoterpene ketones may be utilized aspure enantiomers or mixtures thereof.

As essential oil, peppermint oil (Oleum Menthae crispae) is used withparticular preference.

The content of monoterpene ketone(s) or of essential oils in thenicotine-containing matrix is preferably 0.1 to 5.0%-wt., especiallypreferred 0.5 to 2%-wt.

The invention further relates to a process for masking an unpleasantsmell, caused by a content of nicotine, of a transdermal therapeuticsystem, this process being characterized in that at least oneodour-improving substance is added to the nicotine-containingtransdermal therapeutic system, said substance being an essential oilextracted from a mint species, or being a monoterpene ketone containedin an essential oil extracted from a mint species.

Here, preferably, the monoterpene ketones mentioned above or peppermintoil may be used as monoterpene ketones or essential oil, respectively,it being possible to utilize the monoterpene ketones as pure enantiomersor as mixtures thereof.

The monoterpene ketone(s) or the essential oil(s) of thenicotine-containing matrix are preferably used in a concentration of 0.1to 5.0%-wt, especially preferred in a concentration of 0.5 to 2%-wt.

Further, the invention comprises the use of an essential oil extractedfrom a mint species and/or of a monoterpene ketone contained in anessential oil extracted from a mint species, for masking an unpleasantsmell of a transdermal therapeutic system, said smell being caused by acontent of nicotine in said transdermal therapeutic system.

Preferably, the monoterpene ketone used is one from the group ofcarvone, dihydrocarvone, menthone, isopulegone, isomenthone,neomenthone, neoisomenthone or piperitone, it being possible to use themonoterpene ketones as pure enantiomers or as mixtures thereof.

As essential oil, peppermint oil (Oleum Menthae crispae) is used withparticular preference.

In the use according to the invention for masking an unpleasant smell ofa nicotine-containing transdermal therapeutic system, the monoterpeneketone(s) or the essential oil are/is added to the nicotine-containingmatrix preferably in a concentration of 0.1 to 5.0%-wt, particularlypreferred in a concentration of 0.5 to 2%-wt.

1. Transdermal therapeutic system comprising a backing layer, at leastone nicotine-containing layer or zone, and an additive comprising atleast one monoterpene ketone, wherein the content of at least onemonoterpene ketone in the nicotine-containing layer or zone is 0.1 to5.0%-wt of the weight of the layer or zone.
 2. Transdermal therapeuticsystem according to claim 1, wherein the monoterpene ketone is selectedfrom the group consisting of carvone, dihydrocarvone, menthone,isopulegone, isomenthone, neomenthone, neoisomenthone and piperitone. 3.Transdermal therapeutic system according to claim 2, wherein themonoterpene ketone is a pure enantiomer thereof or a mixture ofenantiomers thereof.
 4. Process for masking an unpleasant smell, causedby the presence of nicotine, comprising adding to a nicotine-containinglayer or zone of a nicotine-containing transdermal therapeutic system,0.1 to 5.0%-wt, based on the weight of the layer or zone, of at leastone monoterpene ketone.
 5. Process according to claim 4, wherein themonoterpene ketone is selected from the group consisting of carvone,dihydrocarvone, menthone, isopulegone, isomenthone, neomenthone,neoisomenthone and piperitone.
 6. Transdermal therapeutic systemaccording to claim 1, wherein the nicotine-containing layer or zone haspressure-sensitive adhesive properties and is covered by a removableprotective layer.
 7. Transdermal therapeutic system according to claim1, wherein the content of the at least one monoterpene ketone in thenicotine-containing layer or zone is 0.5–2%-wt of the weight of thelayer or zone.
 8. Process according to claim 4, wherein the at least onemonoterpene ketone is added to the nicotine-containing layer or zone ina quantity constituting 0.5–2% wt of said layer or zone.